Foscarnet, the tri-sodium salt of phosphonoformic acid, is a potent inhibitor of reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1). It acts by selectively inhibiting viral DNA polymerase and reverse transcriptase. It is not phosphorylated into an active form by viral host cell enzymes. Therefore, it has the advantage of not requiring an activation step before attacking the target viral enzyme. It inhibits reverse transcriptase and is active against HIV and was approved by the FDA for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Foscarnet is also effective in the treatment of mucocutaneous diseases caused by acyclovir-resistant strains of herpes simplex virus (HSV) and varicella-zoster virus (VZV) in AIDS patients.
Foscarnet can only be administrated intravenously because of its very low oral bioavailability. Although Foscarnet has very good water solubility, the poor oral absorption is probably due to its triple negative charge which is an impediment to cellular uptake. Also it is inherently unstable due to the ability of the formic acid moiety contained in the structure to readily decompose into carbon dioxide when introduced to an acidic environment, such as the stomach.
A number of research efforts have been devoted to not only improve the stability but the delivery of Foscarnet intracellularly. For example, Hammond et al describe alkylglycerol derivatives of foscarnet (Alkylglycerol prodrugs of phosphonoformate are potent in vitro inhibitors of nucleoside-resistant human immunodeficiency virus type 1 and select for resistance mutations that suppress zidovudine resistance. Hammond, J.; Koontz, D.; Bazmi, H.; Beadle, J.; Hostetler, S.; Kini, G.; Aldern, K.; Richman, D.; Hostetler, K.; Mellors, J. Antimicrob. Agents Chemother. 2001, 45, 1621-1628). However, there is a large unmet need for developing novel foscarnet-like compounds.
The present invention seeks to address these and other needs in the art.